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Selective, Reversible Inhibitors of the AAA ATPase p97

Selective, Reversible Inhibitors of the AAA ATPase p97

Tsui-Fen Chou, Kelin Li, Brian E. Nordin, Patrick Porubsky, Kevin Frankowski, Mathew P. Patricelli, Jeffrey Aubé, Frank J. Schoenen, Raymond Deshaies

PMID: 23658965

Abstract:

The AAA ATPase p97 is a critical factor in maintaining protein homeostasis in eukaryotic cells, through its roles in promoting degradation of ubiquinated proteins by the proteasome and in maturation of autophagosomes. Starting from a hit obtained by high-throughput screening (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), the team developed probe compounds ML240 and ML241 that both inhibit p97 ATPase activity with an IC50 of approximately 100 nM, and block degradation of p97-dependent proteasome substrate with an IC50 of approximately 900 nM and 3500 nM, respectively. By contrast, these probe compounds were far less potent in blocking degradation of the p97-independent substrate oxygen-dependent degradation domain (ODD)-luciferase (IC50 > 28 μM), underscoring their specificity towards p97. The two probe compounds exhibited markedly different potencies for activating executioner caspases and blocking cell growth. ML240 rapidly induces caspases 3 and 7 in HCT15 and SW403 cells and potently blocked proliferation of these cells, whereas ML241 was >10-fold less efficacious in both assays.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1346527987	ML240		1346527-98-7	Price

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